The present invention is in the field of pharmaceutical delivery systems, and in particular relates to the use of 3'-azido-2',3'-dideoxy-5-methylcytidine and compositions thereof for the inhibition of viral infections.
AIDS was recognized as early as 1979. The number of cases reported to the Centers for Disease Control (CDC) has increased dramatically each year since then, and in 1982 the CDC declared AIDS a new epidemic. AIDS is generally accepted at this time to be a consequence of infection with the retrovirus, human immunodeficiency virus (HIV-1). Antibodies to these viruses are present in over 80% of patients diagnosed as having AIDS or pre-AIDS syndrome, and have been found with high frequency in identified risk groups.
A patient is generally diagnosed as having AIDS when a previously healthy person with an intact immune system acquires impaired T-cell immunity. The impaired immunity usually appears over a period of eighteen months to three years. As a result of this impaired immunity, the patient becomes susceptible to opportunistic infections, various types of cancer such as Kaposi's sarcoma, and other disorders associated with reduced functioning of the immune system.
Another condition associated with the presence of anti-HIV antibodies is AIDS-related complex, or ARC. This condition is thought to lead eventually to AIDS.
A number of compounds have been found to have antiviral activity against this virus, including HPA-23, interferons, ribavirin, phosphonoformate, ansamycin, suramin, imuthiol, penicillamine, rifabutin, AL-721, 3'-azido-3'-deoxythymidine (AZT), and other 2,'3'-dideoxynucleosides, such as 2',3'-dideoxycytidine (DDC), 2',3'-dideoxyadenosine (DDA), 3'-azido-2',3'-dideoxyuridine (AzddU), 2',3'-didehydrocytidine, 3'-deoxy- 2',3'-didehydrothymidine and 3'-azido-5-ethyl-2',3'-dideoxyuridine (AzddEU). The present application is a continuation-in-part of applications directed to both AzddEU and AzddU.
In general, inhibitors of cellular processes will often limit viral replication, but such agents are usually quite toxic for the host as well. Most of the antiviral drugs that have been discovered so far cannot be prescribed for a prolonged period of time because of their toxicity. For example, a compound structurally related to the compounds of the present invention, idoxuridine, is limited in clinical usefulness to topical application in ophthalmic solutions for treatment of herpetic keratitis because of its toxicity to normal cells.
AZT has been studied extensively in humans for treatment of HIV-1 infections. AZT can decrease the frequency of opportunistic infections in a selected group of individuals with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC). However, bone marrow toxicity and other side effects may limit its usefulness. For example, Richman et al. has shown that because of AZT-associated hematological abnormalities, twenty-one percent of patients undergoing AZT therapy required multiple blood transfusions during the six month treatment period. Bone marrow depression may be due to the accumulation of phosphorylated AZT within cells, which may result in a substantial depression of thymidine 5'-triphosphate pools. Another drawback of AZT is its short half life in humans (about 1.1 hour) and its elimination in urine as 3'-azido-3'-deoxy-5'-gluronylthymidine, a metabolite with no substantial antiviral activity.
In light of the state of the art, it is clear that there remains a strong need for new effective antiviral agents, especially those with low toxicity to normal cells. More particularly, in light of the lack of an effective treatment for AIDS and the fact that AIDS patients require a long term therapy, possibly for an entire life span, there remains a great need for development of new antiviral agents of low toxicity for AIDS treatment.
It is therefore an object of the present invention to provide a new antiviral composition that has low toxicity toward uninfected cells.
It is a further object of this invention to provide a composition for inhibiting the replication of HIV-1 and other retroviruses.
It is yet another object of the present invention to provide a method for the prevention and treatment of infection by HIV-1 and other retroviruses.